Chlamydia is the most common cause of sexually transmitted diseases in the USA. As a reportable bacterial pathogen it is a significant medical and public health problem. Chlamydia strains that infect the eye are recognized as one of the seven great neglected diseases of humans. The long-term objectives are to understand the requirements for chlamydial infection of mammalian host cells. This will yield important fundamental information for the development of new approaches for intervention. Like viruses, Chlamydia must infect a mammalian cell to enable their growth and transmission. Thus, delineating the steps in the infection process is fundamental to understanding pathogenesis and virulence and providing new directions for medical treatment and public health control. The infection process is complex and involves cell invasion and subsequent growth and exit mechanisms. The focus of this application is on the first steps of cell infection- microbial attachment and entry. The hypothesis is that host cell surface proteins serve as receptors for chlamydial attachment and this interaction results in protein modifications that trigger entry of the organisms into their host cells. The specific aims include the identification of host surface proteins that are required for Chlamydia attachment and the substrate proteins required for chlamydial entry. The experimental design employs a unique and strong genetic platform for analyzing functional interactions between host cells and chlamydial organisms and also the application of robust biochemical approaches for monitoring and testing disulfide interactions in complex systems. The expected outcome of these studies is the identification of cellular surface components that are necessary for the attachment and uptake processes of chlamydial infection. PUBLIC HEALTH RELEVANCE: The relevance is to gain an understanding of chlamydial infection mechanisms for the development of innovative approaches for intervention. The chlamydial ligand that interacts with cell surface proteins is a target for immune intervention or for inhibitors of steps required for successive steps in infectivity. For example, knowledge of the requirement and target for protein thiol reduction may have future clinical application for the development of suicide substrates for chlamydiae suitable as topical microbicides.